For the past quarter-century, with the high incidence of prostate cancer worldwide, the proportion of early stage prostate cancer has increased. Several treatment options for localized prostate cancer are available including the two standard treatment options, radical prostatectomy, and radiation therapy. Although the treatment outcomes have improved the procedure and devices, the biochemical recurrence rate had not decreased yet    . Recently, many alternative and less invasive treatments have been developed for localized prostate cancer   . Since the first clinical application of HIFU for the treatment of localized prostate cancer by Madersbacher et al.  (using the SçonablateTM 200), several investigations of HIFU therapy using Ablatherm or Sonablate systems have been reported for patients with this disease    . HIFU is a less invasive technique for thermal ablation of tissue that can induce complete coagulation necrosis of a targeted tumor without requiring surgical exposure or insertion of invasive instruments  . Since 2003, we have performed transrectal HIFU therapy for patients with localized prostate cancer, and we have reported the efficacy and safety of HIFU ablation for patients with localized prostate cancer   . According to these experiences, we think HIFU therapy has the advantages of fewer complications, the potential for a repeat treatment, simplicity of the procedure, and shorter treatment times  . Beginning in 2005, we performed focal HIFU at the VUA for 4 patients with PSA failure without distant metastasis after prostatectomy  . Since then, we have experienced an additional 12 cases. Here we retrospectively examined the prognosis and long-term outcomes of the salvage HIFU for total 16 patients with the suspected recurrence of at the VUA.
From May 2005 to May 2016 in our Takanobashi central hospital, we performed salvage HIFU in 16 patients (57 - 83 years old). All patients had PSA failure (over 0.2 ng/ml) after radical prostatectomy. These patients’ characteristics before prostatectomy and before salvage HIFU are shown in Table 1. The median PSA level before radical prostatectomy was 8.4 ng/ml (range; 4.2 - 18). The postoperative pathological stage ranged pT2a - pT3b and Gleason score ranged 5 - 9. The median follow-up period after prostatectomy in these cases was 18 months (range; 8 - 144). Over two-thirds of these prostatectomy patients failed within 12 months after treatment using PSA > 0.2 ng/ml definition. The median PSA level of these 16 patients before HIFU was 0.978 ng/ml (range; 0.318 - 3.1) without androgen deprivation therapy (ADT) after prostatectomy. No distant metastasis or regional lymph node swelling by CT (including 2 PET CTs), MRI (including 4 multiparametric MRIs) and bone scintigaraphy was found before salvage HIFU (Table 2). However, soft mass lesions at the VUA region were found in 6 patients by CT, 13 by MRI, 4 by TRUS and 2 by urethrocystoscope, which caused us to suspect local recurrence. Positive cancer lesion by biopsy was found in 3 patients.
Table 1. Characteristics of 16 patients with salvage focal HIFU.
HIFU: high-intensity focused ultrasound, PSA: prostate specific antigen, D’Amico: D’Amico classification.
Table 2. Data of examinations before therapies in patients with salvage HIFU.
CT: computer tomography, MRI: magnetic resonance imaging, TUR: transrectal resection, LN: lymph node.
Fifteen patients were treated using Sonablate 500® and/or version 4 (Sonacare Medical, Inc., Indianapolis, IN, USA) device under spinal anesthesia, and one with caudal anesthesia. HIFU therapy was performed using the standard transrectal procedure  . In order to confirm the position of the external sphincter at the time of the HIFU treatment, we placed biopsy forceps as a marker at the distal portion of the external sphincter under urethroscopic visualization  . We performed HIFU sonication on the VUA region from the proximal portion of the external sphincter to the bladder neck under ultrasound visualization (Figure 1). Recurrence after salvage HIFU was determined based on PSA failure (PSA > 0.2 ng/ml), histological findings, metastasis and start of ADT. Recurrence free survival (RFS) rate was calculated using Kaplan-Meier curves and a log-rank test was used to evaluate differences between these curves. Mann-Whitney test was used to evaluate statistical difference of two groups. P-value of <0.05 was considered to indicate statistically significant differences. Patient status and treatment-related complications in the Japanese version of the National Cancer Institute-Common Toxicity Criteria version 4.0  were evaluated.
All patients received informed consent of the diagnosis and treatments for suspected recurrence of a VUA lesion. The patients who chose HIFU therapy were provided with the informed consent for particular HIFU treatment and agreed to pay privately for the uninsured therapy in Japan, and the institutional review board for Takanobashi Central Hospital approved these studies.
HIFU therapy was performed in 16 patients. Intraoperative and perioperative results are shown in Table 3. The median HIFU exposure time was 28 min. (range; 9 - 42). The median hospital stay was 2 days (range; 2 - 7) and the median periods of catheterization were 5.5 days (range; 4 - 21). There were no adverse effects observed in the period from HIFU treatment to removal of the indwelling catheter.
Figure 1. Ultrasound images during HIFU. (A) Sonication field in upper half of the urethra in case 2. (B) Marking the distal portion of the external sphincter with a biopsy forceps. (a) Sector section view (b) Linear section view.
Table 3. Intraoperative and perioperative results of HIFU therapy.
The median follow-up period of this study was 46.5 months (range; 7 - 159). As shown in Table 4, the median PSA nadir after HIFU was 0.088 ng/ml (range; 0.008 - 0. 789) at 1.5 median month (range; 1 - 21), and 88% of these PSA were <0.2 ng/ml. The curve of RFS rates were analyzed using the Kaplan-Meier method with PSA level > 0.2 indicating recurrence in Figure 2(A). The RFS rates of 1, 2, 3 and 5 year were 50%, 37.5%, 31.3% and 31.3%. Patients were categorized according to risk group with initial PSA, pathological Gleason score and T-stage in Figure 2(B). There was no difference in the RFS between the intermediate risk (30%) and the high risk (33%) group. Of the 16 patients with salvage HIFU, 4 patients’ PSAs were under 0.2 ng/ml at the latest PSA, one patient’s PSA was <0.2 ng/ml until 115 months after HIFU, and 11 patients’ PSAs were over 0.2 ng/ml until 36 months after HIFU. A small mass was detected by CT and/or MRI before HIFU recurred in ten cases (77%) of the 13 patients. We compared the five effective cases with the early recurrence 11 cases. Although there was no difference in initial PSA (P = 0.141), pretreatment PSA (P = 0.257) and the time to salvage HIFU after prostatectomy (P = 0.363) between the effective 5 cases and the recurrent 11 cases, we recognized significant difference (P = 0.014) in the nadir PSA after HIFU.
Table 4. Results of HIFU therapy in 16 patients with recurrence of vesicourethral anastomosis.
G: Grade of CTCAE v4.
Figure 2. Non-recurrent curves in 16 cases with salvage HIFU. (A) According definition of PSA failure; (B) According risk group with iPSA, p-Gleason score and p-Stage.
The changes of the PSA levels in non-recurrent cases (cases No. 4, 8 and 9) are shown in Figure 3. Their PSA stayed under <0.2 ng/ml for the follow-up periods. Figure 4 shows the changes of the PSA in non-recurrent within 2 years (cases No. 1 and 13). Their PSA remained < 0.4 ng/ml for over 3 years. A temporary rise was usually observed in the PSA level in all patients on the first day after HIFU and a rapid decrease of PSA was seen thereafter.
Adverse effects at 1 - 3 months after HIFU (Table 4) were difficulty with voiding in 4 patients (grade-1) and urinary urgency or incontinence was observed in 3 cases (grade-1; 2, grade-2; 1).
Figure 3. Changes in PSA levels following salvage HIFU therapy in patients with excellent outcome. iPSA: initial PSA -GL: pathological Gleason’s score p-stage: pathological stage.
Figure 4. Changes in PSA levels following salvage HIFU therapy in patients with good outcome.
For the prognosis of these salvage HIFU patients, 6 of 12 patients with PSA failure underwent ADT, 3 underwent re-treatment with HIFU, one was followed-up without therapy and two were unknown. No patients died of prostate cancer, but two died of cardiovascular disease and three patients were lost to follow up. A recto-urethral fistula was not observed in this series.
There are some salvage therapies for recurrence after radical treatment of localized prostate cancer    . For salvage HIFU therapy, although there are many reports for radio-recurrent prostate cancer in recent years    , there are only a few reports   for recurrence after prostatectomy available besides our reports   and those of Murota-Kawano  . After our first report of salvage HIFU therapy for four patients after prostatectomy  , we performed salvage focal HIFU on lesions at the VUA in a total of 16 cases. The advantages of salvage HIFU therapy as well as whole grand HIFU for primary prostate cancer include the following  : no bleeding, less infection, ease of procedure, shorter treatment times, and the possibility of administering repeat treatments. As shown in Figures 3-5, a temporary rise is observed in the PSA level of nearly all patients on the first day after HIFU. These PSA changes appear to confirm the fact that the residual prostate tissue was destroyed in the sonication fields. Further, the rapid decrease of PSA after a temporary rise indicates the effectiveness of HIFU therapy.
The biochemical recurrence free survival (BRFS) of the salvage HIFU after radiation therapy was based on Phoenix definition. In the two large volume reports   about salvage HIFU after failed radiotherapy, the BRFS rates were 48% at 3 years and 49% at 5 years for the entire group. The BRFS rates were 100%, 61% and 32% at 3 years and 58%, 51% and 22% at 5 years in the low-, intermediate- and high-risk groups on pre-salvage HIFU, respectively. Conversely, the salvage HIFU after prostatectomy results in other reports   , effectiveness of this therapy was defined as <0.4 ng/ml PSA level or PSA nadir level. The success rate of these reports at 4 years was 45% - 47%. Although there are differences of proportion of stage, risk group and duration of follow-up as compared to these reports   , our RFS rates using the criteria of 0.2 ng/ml PSA were 31.3% at 3 or 5 years after HIFU. With PSA < 0.4 ng/ml, our RFS rate was 43.8% and 31.3% at 3 and 5 years after HIFU. On the other hand, our RFS rate was 72.7% and 62.3% by the ASTRO definition. Our outcomes were similar to the RFS rate of these reports   .
The main complications for salvage HIFU after radiotherapy are urethral and/or bladder neck stricture at 8% - 18%, and RUF at 2% - 2.3%   . For salvage HIFU after prostatectomy in other reports   , although urethral stricture rate was similar (5% - 10%), the urinary incontinence was higher (21% - 25%) and RUF was not observed. At 1 - 3 months after HIFU, difficulty in voiding and urinary urgency or incontinence was similar (25% and 19% respectively).
Figure 5. Changes in PSA levels following second salvage HIFU therapy in patients with recto-urethral fistula.
Although a recto-urethral fistula (RUF) was not observed in this series, we experienced a RUF in 2 of the 3 patients with a second HIFU treatment. As these adverse events were important, we are presenting the two cases with serious side effects. The changes of PSA levels in the patients (case No. 7, 11) are shown in Figure 5. They underwent a second salvage HIFU treatment because of early recurrence, and a recto-urethral fistula occurred after removal of the urethral catheter. Though they had suprapubic cystostomy, an artificial colostomy and trans-rectal closure, the RUF were not closed completely during follow-up. Patient (No. 7) also underwent a TUR for bladder tumor, and a right nephroureterectomy for ureteral cancer after the second HIFU, and then a total cysto-urethrectomy and left cutaneous ureterostomy due to the recurrence of bladder cancer. The fistula almost healed by the time of the total cystectomy, and no adenocarcinoma was found in the VUA. The RUF of second patient (No. 11) did not close during follow-up. He has undergone ADT and his PSA is still under 2 ng/ml.
We inferred from the experience of our two patients with RUF that the RUF may have been caused by the second HIFU with its high power energy and the delay of treatments for dysuria. Topazio et al.  reported success for RUF with conservative treatment. But our patients could not obtain complete closure even with surgical procedures.
We performed a second salvage HIFU treatment for 3 patients with recurrence, and followed them-up from 112 to 144 months. Although all patients had recurrence, one patient had PSA < 0.2 for more than 4 years and the patient (No. 7) with RUF had PSA < 0.3 ng/ml for more than 4 years and <0.1 ng/ml after cystectomy. Though we cannot evaluate the effectiveness of re-treatment with salvage HIFU because there were only three cases, users should be aware of the risk of RUF.
The limitation in our retrospective study is that there were many patients without biopsy-confirmed local recurrence. As for the histological confirmation, it was difficult to confirm by early biopsy after prostatectomy, especially with PSA < 1.0 ng/ml  or with PSA < 0.5 ng/ml and negative digital rectal examination  . In our cases with no malignancy by biopsy, it is necessary to confirm with another test, such as digital rectal palpation, TRUS or MRI  . Recently, fusion biopsy with TRUS and multiparametric MRI is recommended for diagnosis or recurrence after radical therapy of prostate cancer  . Therefore, we performed these from the proximal portion of the external sphincter to the bladder neck by the placement of a biopsy forceps as a marker, which was inserted to the distal portion of the external sphincter (Figure 1(B)).
In the latest two cases of salvage HIFU, there was suspicion of recurrence on the VUA region by multiparametric MRI, but these lesions could not be proven by transrectal biopsy. In one of the cases discovered by multiparametric MRI, we found that the positive findings disappeared by MRI at 7 months after HIFU. After that, when the PSA rose over 2.0 at 26 months after HIFU, the positive finding appeared in the proximity of the residual seminal vesicle located by MRI.
Asimakopoulos et al.  reported on 19 patients that those patients with lower Gleason scores and lower PSA values had a better outcome than those patients with higher scores and values. In our patients, there was no difference in the RFS rate between the intermediate and the high risk groups. In the comparison with effective cases and early recurrent cases, there was significant difference only in the nadir PSA after HIFU. From these results, we consider that the effectiveness of salvage HIFU is due to sufficient sonication of recurrence areas rather than PSA levels or malignant grade. So it is critical to correctly diagnose the area of recurrence and perform sufficient sonification. Although the predictive factor is a nadir PSA, we cannot determine in advance the patients that will respond favorably to HIFU.
In the cases with no malignancy determined by biopsy, it is necessary to confirm with TRUS and multiparametric MRI. However in the case of prostatectomy, it is hard to diagnosis because of minimal tumor mass (PSA < 1.0 ng/ml)    . Moreover, HIFU therapy is sensitive surrounding blood flow or urine for achieving sufficient temperature   . It is also critical to determine the accurate distance from the rectal mucosa to the VUA.
HIFU therapy for local recurrence after prostatectomy may become a feasible therapeutic salvage option because of its easy and short procedure time. As our study was a retrospective analysis with a low volume cases, further research and additional follow-up are required to evaluate this salvage therapy. Moreover for the best outcomes, correct diagnosis of recurrence areas, sufficient sonication and careful follow-up are necessary.
Abbreviations & Acronyms
ADT = androgen deprivation therapy
ASTRO = American Society for Therapeutic Radiology and Oncology
BRFS = biochemical recurrence free survival
CT = computed tomography
HIFU = high-intensity focused ultrasound
MRI = magnetic resonance imaging
PSA = prostate-specific antigen
RFS = recurrence free survival
RUF = recto-urethral fistula
TRUS = transrectal ultrasound
TU-biopsy = transurethral biopsy
VUA = vesicourethral anastomosis
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